title: Membrane remodeling by α-synuclein and effects on amyloid formation.
abstract: α-Synuclein (α-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ∼20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits α-syn amyloid formation affecting both lag and growth phases. Using five single tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that α-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, Kp ∼ 300 M(-1)). Vesicle deformation by α-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for α-syn induced membrane remodeling related to both function and pathogenesis.
authors.affiliation: Laboratory of Molecular Biophysics, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Jiang
authors.forename: Michel
authors.initials: M
authors.lastname: de Messieres
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D002942:Circular Dichroism; D020404:Glycerophospholipids / Q000737:chemistry; D007202:Indicators and Reagents; D008051:Lipid Bilayers; D008055:Lipids / Q000737:chemistry; D008567:Membranes, Artificial; D046529:Microscopy, Electron, Transmission; D008870:Microtubules; D009502:Neutrons; D010713:Phosphatidylcholines; D013056:Spectrophotometry, Ultraviolet; D014364:Tryptophan / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: C509561:1-palmitoyl-2-oleoyl-phosphatidyl-3-adenosine; D000682:Amyloid; D020404:Glycerophospholipids; D007202:Indicators and Reagents; D008051:Lipid Bilayers; D008055:Lipids; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D051844:alpha-Synuclein; D014364:Tryptophan; D002784:Cholesterol; D000241:Adenosine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine